Project Summary A recent study by the Rand Corporation indicated that methamphetamine (MA) abuse costs the United States over $20-$60 billion/year. About 10 million Americans have used MA at least once. Chronic MA use has far reaching health consequences and a tremendous societal impact. At V.A. Medical Centers MA abuse is associated with increased use of facility resources and deleterious consequences for veterans, such as additional psychiatric disorders. There are currently no approved medications for treatment of MA addiction, and consequently there is an urgent need to discover MA pharmacotherapies. Recently the trace amine-associated receptor 1 (TAAR1) has been identified as a target for MA and its analogues, but not for cocaine. Therefore, TAAR1 is possibly a unique MA target. TAAR1 knockout (KO) mice show increased activity in response to MA and we have shown that they preferentially consume more MA as compared to their wild-type (wt) littermates. Additionally, KO mice, and mice expressing a non-functional TAAR1 are insensitive to the aversive effects of MA (hypothermia, conditioned taste aversion). There are no commercially available selective agonists or antagonists for the TAAR1. Developing new drugs that interfere with MA-mediated effects at TAAR1 has clinical implications in that (partial) agonists could serve as treatments to possibly limit MA intake. Conversely, TAAR1 antagonists can serve as important pharmacological tools to further study of TAAR1-mediated physiology. This project will use a translational approach to characterize cultured cells that express multiple non- synonymous single nucleotide polymorphisms (SNP) of human TAAR1. In addition, we will use viral-mediated gene transfer of human TAAR1 polymorphisms in mice to determine the effects of synthesized novel agents designed to both affect human TAAR1 function and to compete pharmacologically with MA. Results from these experiments will identify the role of TAAR1 in MA-mediated pharmacology and behaviors and will characterize potential new pharmacotherapies, synthesized in our laboratories, which can be used to treat specific symptoms of MA abuse and addiction.